Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Collagen Induced Arthritis (CIA) is a widely studied animal model to develop and test novel therapeutic approaches for treating Rheumatoid Arthritis (RA) in humans. Soluble Cytotoxic T-Lymphocyte Antigen 4 (CTLA4-Ig), which binds B7 molecule on antigen presenting cells and blocks CD28 mediated T-lymphocyte activation, has been shown to ameliorate experimental autoimmune diseases such as lupus, diabetes and CIA. Objective of our research was to investigate in vivo the effectiveness of blocking the B7/CD28 T-lymphocyte co-stimulatory pathway, utilizing a gene transfer technology, as a therapeutic strategy against CIA. Replication-deficient adenoviruses encoding a chimeric CTLA4-Ig fusion protein, or beta-galactosidase as control, have been injected intravenously once at arthritis onset. Disease activity has been monitored by the assessment of clinical score, paw thickness and type II collagen (CII) specific cellular and humoral immune responses for 21 days. The adenovirally delivered CTLA4-Ig fusion protein at a dose of 2x10^8 pfu suppressed established CIA, whereas the control beta-galactosidase did not significantly affect the disease course. CII-specific lymphocyte proliferation, IFNgamma production and anti-CII antibodies were significantly reduced by CTLA4-Ig treatment. Our results demonstrate that blockade of the B7/CD28 co-stimulatory pathway by adenovirus-mediated CTLA4-Ig gene transfer is effective in treating established CIA suggesting its potential in treating RA.
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PMID:[Recombinant adenovirus-mediated gene transfer suppresses experimental arthritis] 1246 78

T cells play a central role in the development of diabetes both in man and in the non-obese diabetic (NOD) mouse. Both the CD4(+) and CD8(+) subsets of T cells are required for the normal development of IDDM in NOD mice. Islet reactive CD4(+) T cells play a clear pathogenic role as evidenced from the isolation of diabetogenic CD4(+) T cell clones. CD8(+) T cells seem to be involved in the initiation of diabetes as lack of these cells leads to protection from diabetes. We have isolated a GAD(65) reactive, cytotoxic CD8(+) T cell clone R1 that produces large quantities of IFNgamma and accelerates the onset of insulitis. This clone proliferates and produces IFNgamma in response to GAD(65) presenting APCs and kills GAD(65) presenting targets. Furthermore, it expresses TNFalpha, CD25, CD28, CD44, CD45 and LFA1, but not CD95L This is the first example of a GAD(65)specific CD8(+) T cell clone that accelerates the onset of the insulitis, although it does not appear to accelerate the onset of diabetes.
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PMID:An islet-homing NOD CD8+ cytotoxic T cell clone recognizes GAD65 and causes insulitis. 1265 23

We have recently described an impaired proliferative response of CD4(+) T-cells to primary antigens in patients with insulin-dependent diabetes mellitus (IDDM) [Clin. Immunol. 103 (2002) 249]. In order to further investigate possible mechanisms underlying this impairment, several factors known to be involved in the down-regulation of the immune response both at the level of APCs and CD4(+) T-cells were investigated: Monocyte-derived dendritic cells (MDDC) from IDDM patients were shown to express elevated amounts of CD86 (B7.2) (p=0.003) and reduced amounts of the adhesion molecule CD54 (ICAM-1) (p=0.03) on their cell surface compared to age-matched healthy controls and patients with non-insulin-dependent diabetes mellitus (NIDDM) as well as decreased SDS-PAGE stability of HLA-DQ and -DR peptide complexes directly isolated from the IDDM patients' peripheral blood mononuclear cells (PBMCs). Expression of CTLA-4 (CD152), known to be involved in the down-regulation of the immune response, was shown to be increased on CD4(+) T-cells from IDDM patients after exposure to the primary antigen KLH (keyhole limpet hemocyanin) presented by MDDC (p=0.0047). Likewise, purified CD4(+) T-cells from IDDM patients produced elevated levels of the cytokine TGF-beta1 after stimulation with immobilized monoclonal antibodies directed against CD3 and CD28 (p=0.014). When monocytes from IDDM patients were stimulated with lipopolysaccharide (LPS), an increased tendency to produce the inhibitory cytokine interleukin (IL)-10 (p=0.007) and the acute phase cytokine IL-6 (p=0.044) was observed, whereas the concentrations of tumor necrosis factor (TNF)-alpha, IL-1beta, and IL-12 were comparable to controls. Taken together, our data suggest that a deviation in the expression of certain molecules known to be involved in the peripheral control of the immune response is present in IDDM patients and is underlying the observed impairment of the primary immune response.
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PMID:Impaired primary immune response in type-1 diabetes. Functional impairment at the level of APCs and T-cells. 1274 78

Once nonobese diabetic (NOD) mice become diabetic, they are highly resistant to islet transplantation. The precise mechanism of such resistance remains largely unknown. In the present study we tested the hypothesis that islet allograft survival in the diabetic NOD mouse is determined by the interplay of diverse islet-specific T cell subsets whose activation is regulated by CD28/CD154 costimulatory signals and the common gamma-chain (gammac; a shared signaling element by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21). We found that common gammac blockade is remarkably effective in blocking the onset and the ongoing autoimmune diabetes, whereas CD28/CD154 blockade has no effect in suppressing the ongoing diabetes. However, CD28/CD154 blockade completely blocks the alloimmune-mediated islet rejection. Also, a subset of memory-like T cells in the NOD mice is resistant to CD28/CD154 blockade, but is sensitive to the common gammac blockade. Nonetheless, neither common gammac blockade nor CD28/CD154 blockade can prevent islet allograft rejection in diabetic NOD mice. Treatment of diabetic NOD recipients with CD28/CD154 blockade plus gammac blockade markedly prolongs islet allograft survival compared with the controls. However, allograft tolerance is not achieved, and all CTLA-4Ig-, anti-CD154-, and anti-gammac-treated diabetic NOD mice eventually rejected the islet allografts. We concluded that the effector mechanisms in diabetic NOD hosts are inherently complex, and rejection in this model involves CD28/CD154/gammac-dependent and -independent mechanisms.
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PMID:Islet allograft rejection in nonobese diabetic mice involves the common gamma-chain and CD28/CD154-dependent and -independent mechanisms. 1450 Jun 90

CD4+CD25+ T cells regulate a variety of autoimmune and alloimmune responses including the development of autoimmune diabetes in non-obese diabetic (NOD) mice. We have examined the role of CD28/CTLA4/B7 interactions in the expansion and survival of CD4+CD25+ regulatory T cells (T(reg)) in this setting. CD28/ B7 interactions are essential in the development of T(reg) in the thymus and for their survival in the periphery. The CD28-mediated homeostasis of these cells is independent of Il2, OX40, CD40L, and survival factor Bcl-XI. In addition, analysis of T(reg) from CTLA4-deficient mice suggests that CTLA4 expression is not required for their development or function. However, non-activating anti-CTLA4 antibodies blocked the suppressor activity of regulatory cells in vitro. Thus, clinical application of co-stimulatory blockade using agents such as CTLA4Ig in the treatment of autoimmune disease may result in complicated outcomes.
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PMID:The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. 1460 12

CBLB was evaluated as a candidate gene for type 1 diabetes (T1D) susceptibility based on its association with autoimmunity in animal models and its role in T-cell costimulatory signaling. Cblb is one of the two major diabetes predisposing loci in the Komeda diabetes-prone (KDP) rat. Cbl-b, a ubiquitin ligase, couples TCR-mediated stimulation with the requirement for CD28 costimulation, regulating T-cell activation. To identify variants with possible effects on gene function as well as haplotype tagging polymorphisms, the human CBLB coding region was sequenced in 16 individuals with T1D: no variants predicted to change the amino-acid sequence were identified. Seven single-nucleotide polymorphism (SNP) markers spanning the CBLB gene were genotyped in multiplex T1D families and assessed for disease association by transmission disequilibrium testing. No significant evidence of association was obtained for either individual markers or marker haplotypes.
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PMID:Polymorphic variation in the CBLB gene in human type 1 diabetes. 1496 Oct 73

AICD of T-cells is an efficient way of removing activated T-lymphocytes. In this study we investigated the molecular basis of AICD upon reactivation in peripheral T-lymphocytes from newly diagnosed T1DM patients and age-matched healthy controls. In an in vitro model system, PHA-stimulated T-cells, upon prolonged culture in IL-2, acquire a sensitive phenotype to Fas-mediated apoptosis. This phenomenon is less pronounced in T1DM T-cells. Moreover, the restimulation of activated T-cells via TCR/CD3 and/or via CD28 inhibits Fas-mediated apoptosis in T1DM in comparison to control T-cells. After Fas triggering, the generation of the active sub-units of caspase-8 is significantly reduced in T1DM T-cells restimulated via TCR/CD3 and/or CD28. In parallel, we found that the amount of c-FLIPshort protein is significantly increased in the DISC only in T1DM T-cells restimulated via TCR/CD3 and via CD28. These data suggest that increased levels of c-FLIPshort may prevent recruitment of pro-caspase-8 in T1DM CD3-treated T-cells and provide new insight into the molecular mechanisms of apoptosis resistance in stimulated T-cells from T1DM patients.
Diabetes Nutr Metab 2004 Feb
PMID:Up-regulation of c-FLIPshort and reduction of activation-induced cell death in T-cells from patients with Type 1 diabetes. 1516 18

The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection. In this study, we describe a robust method to expand antigen-specific Tregs from autoimmune-prone nonobese diabetic mice. Purified CD4+ CD25+ Tregs were expanded up to 200-fold in less than 2 wk in vitro using a combination of anti-CD3, anti-CD28, and interleukin 2. The expanded Tregs express a classical cell surface phenotype and function both in vitro and in vivo to suppress effector T cell functions. Most significantly, small numbers of antigen-specific Tregs can reverse diabetes after disease onset, suggesting a novel approach to cellular immunotherapy for autoimmunity.
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PMID:In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. 1518 99

Autoreactive T cells play a major role in the development of insulin-dependent diabetes mellitus, suggesting that costimulatory molecules that regulate T cell responses might be essential for disease progression. In NOD mice, CD28/B7 and CD40/CD40 ligand (L) interactions control the onset of diabetes from 2 to 4 weeks of age, but blocking these molecules has little effect after this time. Hence, it is possible that other ligand/receptor pairs control a later phase of disease. We now show that OX40 is expressed on CD4 and CD8 T cells several weeks prior to islet destruction, which is initiated around weeks 12-14, and that OX40L is present on dendritic cells in both secondary lymphoid organs and the pancreas from 11 to 13 weeks of age. Blocking OX40L at 6, 9, or 15 weeks after birth had little effect on disease; however, inhibiting OX40/OX40L interactions at week 12, or continuous treatment from week 12 onwards, significantly reduced the incidence of diabetes. Histological examination showed that islet destruction was prevented and insulitis reduced by targeting OX40L. These studies show that OX40/OX40L interactions form a late checkpoint in diabetes development and suggest that these molecules are realistic targets for therapeutic intervention.
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PMID:Prevention of diabetes in NOD mice at a late stage by targeting OX40/OX40 ligand interactions. 1536 74

The development of autoimmune diabetes in the nonobese diabetic (NOD) mouse results from a breakdown in tolerance to pancreatic islet antigens. CD28-B7 and CD40 ligand-CD40 (CD40L-CD40) costimulatory pathways affect the development of disease and are promising therapeutic targets. Indeed, it was shown previously that diabetes fails to develop in NOD-B7-2-/- and NOD-CD40L-/- mice. In this study, we examined the relative role of these 2 costimulatory pathways in the balance of autoimmunity versus regulation in NOD mice. We demonstrate that initiation but not effector function of autoreactive T cells was defective in NOD-B7-2-/- mice. Moreover, the residual proliferation of the autoreactive cells was effectively controlled by CD28-dependent CD4+CD25+ regulatory T cells (Treg's), as depletion of Treg's partially restored proliferation of autoreactive T cells and resulted in diabetes in an adoptive-transfer model. Similarly, disruption of the CD28-B7 pathway and subsequent Treg deletion restored autoimmunity in NOD-CD40L-/- mice. These results demonstrate that development of diabetes is dependent on a balance of pathogenic and regulatory T cells that is controlled by costimulatory signals. Thus, elimination of Treg's results in diabetes even in the absence of costimulation, which suggests a need for alternative strategies for immunotherapeutic approaches.
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PMID:Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells. 1546 37


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